Iron is an essential micronutrient in multiple cellular functions. In addition to its critical role in erythropoiesis, it is also involved in oxygen transport, in the immune cell response, and is particularly important in mitochondria, where it catalyzes enzymatic reactions and regulates oxidative metabolism.1–6 The homeostasis of iron metabolism is dependent on several mechanisms and iron is obtained from two main sources: diet and recycling of senescent erythrocytes.7

Dietary iron is absorbed in the jejunum via a specific transporter.1,3,8 When the body needs iron, it is released into circulation through ferroportin, binding to transferrin so that it can be transported in plasma.1,3,8 Unused iron is stored in the liver, spleen and bone marrow in the form of ferritin.1,3,8

Ferritin is involved in several physiological and pathological cellular processes and is often used as a serum marker of iron stores. It plays an important role in both the diagnosis and follow-up of IDef.9–12

Hepcidin is a hormonal regulator of iron homeostasis; it inhibits ferroportin, thus decreasing gastrointestinal absorption of iron and, as a consequence, it is no longer released from macrophages and hepatocytes. This then leads to a decrease in iron concentration in the blood and in its availability for cell metabolism.1,5,7,11,13

Iron deficiency is a common condition and can be classified as absolute or functional.1,5,13 Absolute IDef is caused by depleted iron stores, possible causes being insufficient iron intake, gastrointestinal malabsorption and/or hemorrhage, resulting in ferritin levels <100 ug/L.1,8,13 Functional IDef results from decreased iron bioavailability compared to demand, despite reserves having adequate levels, due to the increased production of hepcidin.1,5,8,13 It usually results in ferritin levels of 100–299 ug/L and transferrin saturation (TSAT) <20%.1,8 Anemia can result from depleted iron reserves, however, in numerous situations, despite the decrease in these reserves, hemoglobin values are at levels considered normal.3 Usually, anaemia stablishes when there is an important decrease in iron reserves.3

Particular importance was given to adequate levels of iron when it was found that both a deficit and excess of iron alter intracellular functions, especially in the mitochondria, leading to increased oxidative stress and deranged energy metabolism.4,8,11

Cells with high energy requirements, such as cardiomyocytes, have additional signaling pathways compared to storage cells, thus increasing iron reabsorption and decreasing extracellular flux in the case of iron deficiency.1,3,4

The pathophysiology associated with cardiac remodeling in IDef is not yet well-defined. However, in mice with IDef, left ventricular (LV) dimensions are increased associated with mitochondrial changes and sarcomere organisation.14,15 In addition, anemia with IDef causes cardiac hypoxia and fibrosis, factors that also contribute to cardiac dysfunction.14

Iron metabolism disorders are common in patients with heart disease.4,16,17 Of these, the most widely substantiated is chronic heart failure (CHF) and, in these patients, the most common cause of anemia is IDef.14,16,18,19 According to current recommendations, these patients should undergo testing that includes serum iron, serum transferrin, TSAT and ferritin, regardless of the presence or absence of anemia, since IDef may be present many years before anemia develops.4,5,20,21 The role of iron in this disease has been widely studied in recent years, demonstrating that the greater the IDef, the more common and more severe adverse cardiovascular events are.5,22

Intravenous iron supplementation is indicated in patients with CHF and reduced EF who have both absolute and functional IDef.5,18,21,23Although oral iron supplementation can be considered, especially if the condition is not acute, unstable or symptomatic, intravenous over oral supplementation has been demonstrated to be superior.5,6,22 This is mainly due to the interference of CHF inflammation in the absorption of oral iron (by altering the actions of hepcidin and ferroportin). It has been proven that patients with CHF and reduced EF – regardless of the presence of anemia – benefit from the administration of ferric carboxymaltose, showing improvement in New York Heart Association (NYHA) functional class and exercise capacity.2,8,18,21,23,24

Acute coronary syndromes (ACS) are among the most frequent causes of death worldwide.25 They are characterized by an acute clinical status compatible with myocardial ischemia, which may result in cardiomyocyte necrosis.26 They may present as: acute myocardial infarction with (STEMI) or without ST-segment elevation (NSTEMI) or unstable angina; all of them potentially fatal.27,28

Contrary to what has been found in CHF, data in the literature are scarce on the role of IDef in ACS. Given its prevalence and associated morbidity and mortality, it is relevant to assess to what extent iron metabolism disorders have prognostic impact in these patients.16,29

The main objective of this study was to determine the prevalence and prognostic impact of IDef in patients with ACS by assessing the occurrence of death or development of severe HF. It also sought to assess whether IDef adds additional predictive power in the risk stratification of patients with ACS, regardless of the presence of anemia.

An observational longitudinal design study with retrospective data collection was conducted. It had a descriptive and an analytical component.

The main finding of this study was that IDef was an independent predictor of death or severe HF in a population of ACS patients.

In addition,IDef enabled the additional stratification of the prognosis of the patients without anemia for the occurrence of death or severe HF and of those with lower Killip classes (≤2) in terms of occurrence of death.

Additionally, this study showed that IDef is a prevalent condition in a population of ACS patients.

The results of this study corroborate what is currently known in the HF patient population, in which IDef, independent of anemia, is associated with higher morbidity and mortality, a higher number of hospital admissions, and worse quality of life.2,4,5,18

For this reason, current HF guidelines recommend laboratory testing for all patients with HF to diagnose IDef and to start iron supplementation in those with reduced EF, preferably intravenously and with carboxymaltose, regardless of the presence of anemia.3,21,23

Data in the literature are still scarce regarding the IDef in the population of patients with ACS. One of the first studies published on this topic showed that IDef was a determinant of functional capacity and health-related quality of life 30 days after ACS.17 This study included a small number of patients (n=244) and involved a short 30-day period follow-up. It focused on the assessment of functional capacity and quality of life, with and IDef was a predictor of functional capacity and quality of life but not of cardiovascular morbidity and mortality.17 The present study, on the other hand, included a larger sample, a short and long term prognostic assessment (minimum follow-up of one year) and demonstrated the impact of IDef on the occurrence of death, and was and independent predictor of death and severe HF together with other well-known predictors in ACS.25,26,32–34 In that study, the prevalence of IDfe was 46%,17 slightly higher than that reported in our study (36%).

One of the reasons for the high prevalence of IDef in patients with ACS, up to 61% in a recent study, is related to blood loss during invasive procedures and the use of anti-thrombotic therapy.16,20,29 It has been shown that drops in hemoglobin and in the serum iron levels increase mortality. However, in that study it was not possible to show IDef as an independent predictor of death.16

The prevalence of anemia in this study was 4.5%, lower than that found in our study (12.7%). It is known that anemia is a very common condition in hospitalized patients; it cited as a factor of poor prognosis and an important predictor of death both in patients with ACS and in those with HF.16,21,33,35,36,37–40 Its prevalence at admission in patients with ACS seems to range from 17%–28%, increasing over the course of hospitalization.16

In the last two years, some studies assessing the role of IDef in the prognosis of patients hospitalized with ACS have been published.39–42One such study published in 2018 included 836 patients, 29.1% of whom had IDef, with a higher prevalence in women and in patients with anemia.41 After a mean follow-up of four years, IDef was shown to be a strong predictor of non-fatal AMI and cardiovascular mortality in this patient population. In view of results from this study and the evidence already available in the literature on the efficacy of iron supplementation in HF with reduced EF, the same authors conducted a multicenter randomized controlled study, the CAYAN trial (Comprehensive management of iron deficiency in myocardial infarction).43 In this trial, patients with clinically relevant AMI and concomitant IDef were randomized to receive iron carboxymaltose or placebo (saline solution). All patients underwent cardiac magnetic resonance imaging at baseline and follow-up to assess the primary endpoint (change in LVEF at baseline and fourth month of follow-up). It should be noted that the aforementioned published studies assessed the IDef at baseline as a landmark to define the groups with and without IDef and to assess the respective prognoses. As in this study, no analysis of iron supplementation at follow-up and its possible correction, as well as its influence on long term prognosis was performed, so that the results of this trial may be important in changing the approach of patients with ACS and IDef.

In another study published in 2019, which included 420 patients with STEMI, the association of IDef with in-hospital mortality and Killip class 3 and 4 was assessed. In this study, a paradoxical result was obtained, in which patients with IDef had better in-hospital prognosis.42

In the present study, anemia was also a predictorof poor prognosis. In order to assess whether the relationship between IDef and prognosis was independent from anemia, in addition to the logistic regression analysis previously described, we divided the sample into two groups (with anemia and without anemia at admission) and compared the incidence of death in patients with and without IDef. It was found that, regardless of the presence of anemia, patients with IDef had higher mortality than patients without IDef. The differences were however not statistically significant, which is possibly related to the low number of deaths in the sample. However, in the stratification of risk of death or development of severe HF, the group without anemia but with IDef had a higher rate of events than those without IDef. A possible explanation for this result may be that iron is not only important in hematopoiesis, but also affects cellular metabolism due to its extensive action in various enzymatic reactions, induction of oxidative stress, and may even cause structural changes in cardiomyocytes, affecting ventricular remodeling and worsening LV function, which consequently leads to worse prognosis.4,8,11,14,15 This result corroborates the HF guidelines, which recommend iron suplementation in patients with IDef even in the absence of anemia. In patients with anemia, there was a higher rate of death or severe HF in patients with IDef, although it was not statistically significant.

Similarly, in order to study the role of IDef in patients with ACS according to the presence or absence of HF, the sample was divided into two groups: patients with Killip Class I–II and those with Killip Class III–IV. In those with Killip Class I–II, IDef enabled additional stratification according to risk of death, revealing a higher mortality rate in those with IDeF. One of the possible explanations for this outcome may be related to alterations in the immune cell response triggered by IDef, in addition to the deranged energy metabolisms already described.1,3,4,8,11 This result highlights the importance of IDef even in the absence of HF or mild HF in the ACS patient population. In patients with Killip Class III–IV, although there was a higher mortality in those with IDef, this result was not statistically significant, which may be due to the low number of patients included in this group and/or the low number of events that occurred.

Different from the HF guidelines, the ACS guidelines do not recommend the evaluation of the iron kinetics to search for IDef.25,26 This study shows the importance of descriminate these patients and futute studies may show the impact of iron suplementation in their prognosis.

This is a single-center retrospective study with all the known inherent limitations. In addition, only one set of iron kinetic parameter tests was used, making it impossible to assess their evolution over time. Also, no therapeutic follow-up assessment was carried out, especially regarding possible iron supplementation. Finally, some patients were excluded due to the absence of iron kinetic parameters, which may be considered as study bias.

This study showed that IDef is a prevalent condition in a population of ACS patients and that, in this population, it was an independent predictor of death or severe HF. Moreover, IDef allowed additional stratification of patients without anemia on admission based on the occurrence of death or severe HF and of those with lower Killip classes (≤2) based on the occurrence of death.

These results may have an impact on clinical practice, especially if further studies attest to an improved prognosis for these patients after iron supplementation.

The authors have no conflicts of interest to declare.